Executive control processes, such as sustained attention, response inhibition, and error processing, allow humans to guide behaviour in appropriate, flexible, and adaptive ways. The consequences of executive dysfunction can be dramatic, as exemplified in a large range of neurological and neuropsychiatric disorders. Such impairments of executive function are responsive to pharmacological treatment, but we lack a comprehensive understanding of the contributions of particular neurotransmitter systems to the processes underlying executive functions, hampering efforts to develop new and more effective treatments. Research to date has implicated the monoamine neurotransmitters dopamine, noradrenaline and serotonin in the processes underlying executive function, but differences between studies in terms of tasks, drug doses and participant groups have limited our ability to judge the relative contributions of these neurotransmitters and to elucidate their precise roles.
The study presented in this thesis sought to address this deficit of knowledge by employing a double-blinded, placebo-controlled, within-subjects, cross-over study design in order to directly compare the behavioural and electrophysiological effects of manipulating monoamine neurotransmitters. This manipulation was achieved with three clinically relevant drugs –methylphenidate, atomoxetine and citalopram – which were chosen for their clinical relevance and their abilities to augment levels of the monoamines of interest. Methylphenidate is dopaminergic and noradrenergic in action, atomoxetine is primarily noradrenergic in action, and citalopram is primarily serotonergic in action. Performing this study within one group of non-clinical participants allowed for the investigation and comparison of monoamine contributions to multiple executive processes. Behavioural and electroencephalographic (EEG) data were obtained for analysis, and the excellent temporal resolution of the EEG method allowed for precise examination of drug effects on physiological markers of executive processes.
The results of this study, divided according to experiments that probe different executive functions, are presented across three chapters. Chapter 4 reports on results regarding error processing and performance monitoring: the processes by which the brain monitors behavioural performance, recognises the commission of errors, and adapts behaviour to improve future performance. Two key event-related potentials were examined – the error-related negativity (ERN) and the error positivity (Pe), which are thought to index pre-conscious and conscious error monitoring. In this experiment, only methylphenidate improved participants’ performance accuracy. Furthermore, methylphenidate increased the amplitude of the ERN, whereas atomoxetine and citalopram did not. There was no effect of drug on the Pe. The effects of methylphenidate in this study reinforce our understanding of theoretical accounts of error processing which emphasise the importance of subcortical dopaminergic contributions to the neural processes of this executive function.
Chapter 5 reports on results concerning response inhibition, the ability to suppress or cancel actions when the environment changes in a way that renders such actions inappropriate. Again, our understanding of the neurophysiological processes underpinning it, and how they are influenced by specific neurotransmitters, is limited. The current study probed response inhibition using a paradigmatic measure of inhibition, the stop-signal task. Behaviourally, no effect of drug was found. However, methylphenidate significantly increased the amplitude of the N2 component on trials on which participants failed to inhibit their response. Furthermore, the ERN elicited on failed inhibition trials was also augmented by methylphenidate. The results are discussed with consideration to the different cognitive processes that may be elicited by the paradigm.
The ability to sustain attention over extended periods of time in the absence of exogenous stimulation is critical to the successful performance of many everyday tasks, and lapses of attention can have dire consequences. Recent research has begun to uncover the importance of neural activity preceding errors that arise due to lapses of attention, with specific neural signatures being predictive of such lapses. Chapter 6 reports the first investigation of how these neural signatures could be modulated by monoamine neurotransmitters. Results extended our knowledge of the maladaptive neural activity associated with attentional lapse and revealed important information about how this activity is influenced by monoamines. Among results reinforcing our understanding of the neural antecedents of attentional lapse and the monoaminergic modulation of neural activity, perhaps of particular interest was the drug effect on oscillatory activity in the alpha band: while there was a significant increase in alpha power prior to missed targets (compared to detected targets) under citalopram, atomoxetine and placebo, this difference was ameliorated by methylphenidate. The results here suggest a critical role for dopamine and noradrenaline in the maintenance of sustained attention.
The research presented in this thesis highlights the complexity of the neural processes underpinning higher order cognitive functions and the neurochemistry that modulates them. Results provided new insight into the neurochemical bases of these processes, improving our understanding of the neural mechanisms of executive control and providing guidance for the development of more effective treatments for disorders characterised by deficits of executive function.